Circulating Markers of Inflammation Persist in Children and Adults With Giant Aneurysms After Kawasaki Disease

Abstract

Background: The sequelae of Kawasaki disease (KD) vary widely with the greatest risk for future cardiovascular events among those who develop giant coronary artery aneurysms (CAA). We sought to define the molecular signature associated with different outcomes in pediatric and adult KD patients. Methods: Molecular profiling was conducted using mass spectrometry–based shotgun proteomics, transcriptomics, and glycomics methods on 8 pediatric KD patients at the acute, subacute, and convalescent time points. Shotgun proteomics was performed on 9 KD adults with giant CAA and matched healthy controls. Plasma calprotectin was measured by ELISA in 28 pediatric KD patients 1 year post-KD, 70 adult KD patients, and 86 healthy adult volunteers. Results: A characteristic molecular profile was seen in pediatric patients during the acute disease, which resolved at the subacute and convalescent periods in patients with no coronary artery sequelae but persisted in 2 patients who developed giant CAA. We, therefore, investigated persistence of inflammation in KD adults with giant CAA by shotgun proteomics that revealed a signature of active inflammation, immune regulation, and cell trafficking. Correlating results obtained using shotgun proteomics in the pediatric and adult KD cohorts identified elevated calprotectin levels in the plasma of patients with CAA. Investigation of expanded pediatric and adult KD cohorts revealed elevated levels of calprotectin in pediatric patients with giant CAA 1 year post-KD and in adult KD patients who developed giant CAA in childhood. Conclusions: Complex patterns of biomarkers of inflammation and cell trafficking can persist long after the acute phase of KD in patients with giant CAA. Elevated levels of plasma calprotectin months to decades after acute KD and infiltration of cells expressing S100A8 and A9 in vascular tissues suggest ongoing, subclinical inflammation. Calprotectin may serve as a biomarker to inform the management of KD patients following the acute illness.

Biomarkers for the Discrimination of Acute Kawasaki Disease From Infections in Childhood

“…These authors found that the endothelium of the coronary arteries from the myocardial sections of three deceased KD patients were almost completely coated when stained with antibodies against MRP8 or MRP14 (S100A8 or S100A9). Recent investigation using a proteomic approach documented elevated levels of MRP8/14 decades after acute KD in patients with giant aneurysms ( 29 ). The variations in the correlations with CAA development may depend on technical differences in measuring CAA dimensions, but more likely will be determined by statistical power (or lack thereof) because of the small sample size of these studies, the non-prospective study design, and maybe also because of genetic differences in the cohorts tested.…”

Kawasaki disease: pathophysiology and insights from mouse models

“…Alarmins from the S100 protein family, which are present in the cytoplasm of neutrophils, monocytes and macrophages 82 , also participate in this inflammatory process. Concentrations of circulating S100A8/A9 hetero dimers (calprotectin) and S100A12 are substantially higher in patients with Kawasaki disease during the acute phase than in control patients with other febrile illnesses and decline after IVIG treatment [83][84][85] . After the acute phase of Kawasaki disease, plasma concentrations of S100A8/A9 heterodimers only remain elevated in patients with giant CAAs 84 , highlighting its potential utility as a biomarker to monitor long-term persistence of inflammation.…”

“…Concentrations of circulating S100A8/A9 hetero dimers (calprotectin) and S100A12 are substantially higher in patients with Kawasaki disease during the acute phase than in control patients with other febrile illnesses and decline after IVIG treatment [83][84][85] . After the acute phase of Kawasaki disease, plasma concentrations of S100A8/A9 heterodimers only remain elevated in patients with giant CAAs 84 , highlighting its potential utility as a biomarker to monitor long-term persistence of inflammation. S100A12 also contributes to the acute inflammatory response by directly stimulating monocytes to produce IL-1β, which in turn activates coronary endothelial cells 85 .…”

Neutrophil-to-lymphocyte ratio and scoring system for predicting coronary artery lesions of Kawasaki disease

“…Otherwise, a large aneurysm can develop and lead to mortality and morbidity. Levels of calprotectin are elevated in pediatric patients with giant coronary artery aneurysms one-year post-KD [10]. Improved diagnostic tools and the development of riskspecific anti-inflammatory treatments have enabled intervention research for people at ultra-high risk.…”